Distinct alleles of the human Ha-ras locus may be identified because of a restriction fragment length polymorphism. We have used this marker to characterize the Ha-ras alleles present in the normal population and the frequency with which new alleles will appear as the population study is expanded (less than 0.01). We have now begun to analyze the Ha-ras locus in normal DNA from individuals with strongly positive family histories of cancer and in DNA from leukemias and solid tumors. Our preliminary results indicate that new alleles appear in solid tumor DNAs far more frequently than expected from the normal population data (30,000 to 1 odds against chance occurrence), while the Ha-ras locus in leukemias is indistinguishable from controls. At least one high-risk family with a familial melanoma syndrome demonstrates an unusual Ha-ras allele and locus structure. Based on these results, we intend to explore the use of polymorphism analysis in tumor risk assessment and the prediction of tumor behavior. We will conduct a study of paired DNA samples from patients white blood cells and tumors to determine if the appearance of new alleles in solid tumors indicates tumor rearrangement of Ha-ras or the existence of genes associated with increased tumor risk. Rearranged alleles will be cloned; adjacent sequences will be analyzed to determine their identity, map positions, and potential effect on Ha-ras expression. DNA from individuals from cancer-prone families will be screened to identify high-risk alleles. Finally, we will determine if oncogene polymorphism analysis can be used to study genomic instability in tumor cells and, ultimately, to predict such aspects of tumor biology as invasiveness, propensity to metastasize, and potential response to therapy. (X)